Regulation of Peroxisome Proliferator-Activated Receptors by E6-Associated Protein

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined. E6-AP inhibited the ligand-independent transcriptional activity of PPARαand PPARβ, with marginal effects on PPARγ, and decreased basal mRNA levels of PPARαtarget genes. Inhibition of PPARαactivity required the ubiquitin ligase function of E6-AP, but occurred in a proteasome-independent manner. PPARαinteracted with E6-AP, and in mice treated with PPARαagonist clofibrate, mRNA and protein levels of E6-AP were increased in wildtype, but not in PPARαnull mice, indicating a PPARα-dependent regulation. These studies suggest coordinate regulation of E6-AP and PPARα, and contribute to our understanding of the role of PPARs in cellular metabolism.

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The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

International Journal of Molecular Sciences ◽

10.3390/ijms22031478 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1478

Author(s):

Jiayin Lu ◽

Yaoxing Chen ◽

Zixu Wang ◽

Jing Cao ◽

Yulan Dong

Keyword(s):

Oxidative Stress ◽

Stromal Cells ◽

Restraint Stress ◽

Target Genes ◽

Mrna Levels ◽

Endometrial Stromal Cells ◽

Protein Levels ◽

Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

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The metabolic coregulator RIP140: an update

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00243.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. E335-E340 ◽

Cited By ~ 53

Author(s):

Asmaà Fritah ◽

Mark Christian ◽

Malcolm G. Parker

Keyword(s):

Nuclear Receptors ◽

Posttranslational Modifications ◽

Energy Homeostasis ◽

Target Genes ◽

Peroxisome Proliferator ◽

Transcriptional Coregulator ◽

Peroxisome Proliferator Activated Receptors ◽

Direct Regulation

RIP140 is a transcriptional coregulator highly expressed in metabolic tissues where it has important and diverse actions. RIP140-null mice show that it plays a crucial role in the control of lipid metabolism in adipose tissue, skeletal muscle, and the liver and is essential for female fertility. RIP140 has been shown to act as a ligand-dependent transcriptional corepressor for metabolic nuclear receptors such as estrogen-related receptors and peroxisome proliferator-activated receptors. The role of RIP140 as a corepressor has been strengthened by the characterization of RIP140-overexpressing mice, although it emerges through several studies that RIP140 can also behave as a coactivator. Nuclear localization of RIP140 is important for controlling transcription of target genes and is subject to regulation by posttranslational modifications. However, cytoplasmic RIP140 has been shown to play a role in the control of metabolism through direct regulation of glucose transport in adipocytes. In this review, we focus on recent advances highlighting the growing importance of RIP140 as a regulator of energy homeostasis.

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Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations

Molecular and Cellular Biology ◽

10.1128/mcb.25.14.6065-6076.2005 ◽

2005 ◽

Vol 25 (14) ◽

pp. 6065-6076 ◽

Cited By ~ 87

Author(s):

Emmanuel Compe ◽

Pascal Drané ◽

Camille Laurent ◽

Karin Diderich ◽

Cathy Braun ◽

...

Keyword(s):

Target Genes ◽

Genetic Disorders ◽

Peroxisome Proliferator ◽

Wild Type ◽

Independent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Pol Ii ◽

Knowing That ◽

Peroxisome Proliferator Activated Receptors ◽

Ppar Ligands

ABSTRACT Mutations in the XPD subunit of TFIIH give rise to human genetic disorders initially defined as DNA repair syndromes. Nevertheless, xeroderma pigmentosum (XP) group D (XP-D) patients develop clinical features such as hypoplasia of the adipose tissue, implying a putative transcriptional defect. Knowing that peroxisome proliferator-activated receptors (PPARs) are implicated in lipid metabolism, we investigated the expression of PPAR target genes in the adipose tissues and the livers of XPD-deficient mice and found that (i) some genes are abnormally overexpressed in a ligand-independent manner which parallels an increase in the recruitment of RNA polymerase (pol) II but not PPARs on their promoter and (ii) upon treatment with PPAR ligands, other genes are much less induced compared to the wild type, which is due to a lower recruitment of both PPARs and RNA pol II. The defect in transactivation by PPARs is likely attributable to their weaker phosphorylation by the cdk7 kinase of TFIIH. Having identified the phosphorylated residues in PPAR isotypes, we demonstrate how their transactivation defect in XPD-deficient cells can be circumvented by overexpression of either a wild-type XPD or a constitutively phosphorylated PPAR S/E. This work emphasizes that underphosphorylation of PPARs affects their transactivation and consequently the expression of PPAR target genes, thus contributing in part to the XP-D phenotype.

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PPARs Integrate the Mammalian Clock and Energy Metabolism

PPAR Research ◽

10.1155/2014/653017 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 86

Author(s):

Lihong Chen ◽

Guangrui Yang

Keyword(s):

Energy Metabolism ◽

Nuclear Receptors ◽

Essential Role ◽

Target Gene ◽

Target Genes ◽

Circadian Regulation ◽

Peroxisome Proliferator ◽

Mouse Tissues ◽

Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of numerous target genes. PPARs play an essential role in various physiological and pathological processes, especially in energy metabolism. It has long been known that metabolism and circadian clocks are tightly intertwined. However, the mechanism of how they influence each other is not fully understood. Recently, all three PPAR isoforms were found to be rhythmically expressed in given mouse tissues. Among them, PPARαand PPARγare direct regulators of core clock components, Bmal1 and Rev-erbα, and, conversely, PPARαis also a direct Bmal1 target gene. More importantly, recent studies using knockout mice revealed that all PPARs exert given functions in a circadian manner. These findings demonstrated a novel role of PPARs as regulators in correlating circadian rhythm and metabolism. In this review, we summarize advances in our understanding of PPARs in circadian regulation.

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The Role of PPARs in Disease

Cells ◽

10.3390/cells9112367 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2367

Author(s):

Nicole Wagner ◽

Kay-Dietrich Wagner

Keyword(s):

Target Genes ◽

Peroxisome Proliferator ◽

Downstream Target ◽

Novel Approach ◽

Pparγ Agonists ◽

Cell Type Specific ◽

Peroxisome Proliferator Activated Receptors ◽

Specific Regulation ◽

X Receptors

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARβ/δ in cancer. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.

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Nutrigenomic Functions of PPARs in Obesogenic Environments

PPAR Research ◽

10.1155/2016/4794576 ◽

2016 ◽

Vol 2016 ◽

pp. 1-17 ◽

Cited By ~ 8

Author(s):

Soonkyu Chung ◽

Young Jun Kim ◽

Soo Jin Yang ◽

Yunkyoung Lee ◽

Myoungsook Lee

Keyword(s):

Target Genes ◽

Current Knowledge ◽

Critical Role ◽

Bioactive Molecules ◽

Metabolic Adaptation ◽

Peroxisome Proliferator ◽

Beige Adipocytes ◽

Peroxisome Proliferator Activated Receptors ◽

Obesogenic Environments

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities.

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DHA Upregulates FADS2 Expression in Primary Cortical Astrocytes Exposed to Vitamin A

Physiological Research ◽

10.33549/physiolres.933708 ◽

2018 ◽

pp. 663-668 ◽

Cited By ~ 2

Author(s):

B. DZIEDZIC ◽

D. BEWICZ-BINKOWSKA ◽

E. ZGORZYNSKA ◽

D. STULCZEWSKI ◽

L. WIETESKA ◽

...

Keyword(s):

Gene Expression ◽

Vitamin A ◽

Dietary Fatty Acids ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Gene Encoding ◽

Protein Levels ◽

Peroxisome Proliferator Activated Receptors ◽

X Receptors ◽

Δ6 Desaturase

The fads2 gene encoding Δ6-desaturase, the rate-limiting enzyme of the LCPUFA biosynthesis is expressed in astrocytes. Dietary fatty acids, which cross the blood-brain barrier, may regulate the transcription of lipogenic enzymes through activation of transcription factors such as peroxisome proliferator-activated receptors (PPARs). The PPARs form the transcription complex with retinoid X receptors (RXRs) that are activated by 9-cis retinoic acid, a metabolite of vitamin A (VA). The study examines whether challenge of astrocytes with VA, prior 24-h treatment with palmitic acid (PA), α-linolenic acid (ALA) or docosahexaenoic acid (DHA) has the effect on the FADS2 expression. RT-qPCR showed that in astrocytes not challenged with VA, PA increased fads2 gene expression and DHA decreased it. However, in VA-primed astrocytes, PA doubled the FADS2 mRNA levels, while DHA increased fads2 gene expression, oppositely to non-primed cells. Furthermore, similar changes were seen in VA-primed astrocytes with regard to Δ6-desaturase protein levels following PA and DHA treatment. ALA did not have any effect on the FADS2 mRNA and protein levels in either VA-primed or non-primed astrocytes. These findings indicate that in the presence of vitamin A, DHA upregulates fads2 gene expression in astrocytes.

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IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

Biomolecules ◽

10.3390/biom10060895 ◽

2020 ◽

Vol 10 (6) ◽

pp. 895 ◽

Cited By ~ 1

Author(s):

Adrianna Moszyńska ◽

James F. Collawn ◽

Rafal Bartoszewski

Keyword(s):

Endothelial Cells ◽

Target Genes ◽

Umbilical Vein ◽

Mrna Levels ◽

Endonuclease Activity ◽

Independent Manner ◽

Protein Levels ◽

The Unfolded Protein Response ◽

Umbilical Vein Endothelial Cells ◽

Sirna Knockdown

While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner.

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Protective role of estrogen against excessive erythrocytosis in Monge’s disease

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00550-2 ◽

2021 ◽

Vol 53 (1) ◽

pp. 125-135

Author(s):

Priti Azad ◽

Francisco C. Villafuerte ◽

Daniela Bermudez ◽

Gargi Patel ◽

Gabriel G. Haddad

Keyword(s):

High Altitude ◽

Messenger Rna ◽

Target Genes ◽

Protective Role ◽

Mrna Levels ◽

Protein Levels ◽

Hypoxic Conditions ◽

Andean Population

AbstractMonge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a+ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.

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New trends in the pharmacological intervention of PPARs in obesity: Role of natural and synthetic compounds_

Current Medicinal Chemistry ◽

10.2174/1570162x18666201123114934 ◽

2020 ◽

Vol 28 ◽

Author(s):

Seyed Mohammad Nabavi ◽

Kasi Pandima Devi ◽

Sethuraman Sathya ◽

Ana Sanches-Silva ◽

Listos Joanna ◽

...

Keyword(s):

Tissue Expression ◽

Health Concern ◽

Pharmacological Intervention ◽

Peroxisome Proliferator ◽

Expression Of Genes ◽

Ppar Agonists ◽

Prevalence Of Obesity ◽

Peroxisome Proliferator Activated Receptors ◽

Natural And Synthetic

: Obesity is a major health concern for a growing fraction of the population, with the prevalence of obesity and its related metabolic disorders not being fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue, leads to the pathogenesis of obesity related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. In the whole, the collected data show that there are both natural and synthetic compounds that show beneficial promising activity as PPAR agonists in chronic diseases related to obesity.

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